TWI812602B - Orally disintegrating tablet containing diamine derivative and producing method thereof - Google Patents

Abstract

An orally disintegrating tablet containing edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof is provided.

An orally disintegrating tablet, which contains: (A) edoxaban, its pharmacologically acceptable salt, or its solvate, (B) organic acid, (C) 0.1 to 2.0 based on the total weight of the tablet % by weight of water-soluble polymer, and (D) disintegrating agent.

Description

Orally disintegrating tablets containing diamine derivatives and manufacturing method thereof

The present invention relates to an orally disintegrating tablet and a manufacturing method thereof. The orally disintegrating tablet contains edoxaban (edoxaban), a pharmacologically acceptable salt thereof, or a solvate thereof. It disintegrates quickly in water and has sufficient hardness when generally manufactured, transported, and used.

Tablets, capsules, granules, powders, etc. are known as dosage forms for oral solid preparations in the fields of pharmaceuticals and foods. However, it is expected to develop formulations that rapidly disintegrate when held in the mouth or put into water. Orally disintegrating tablets are a dosage form that is easier to take for the elderly, children, and patients who cannot swallow.

Orally disintegrating tablets need to have the characteristics of rapid disintegration in the oral cavity, and also need to have sufficient hardness to withstand physical impact during manufacturing, transportation, and use like ordinary tablets. In addition, in terms of medication compliance, it is also expected that the drug will have a good taste while suppressing unpleasant taste and irritation when held in the mouth.

There have been various reports on oral disintegrating tablets. For example, Patent Document 1 describes an orally disintegrating tablet containing a drug, crystalline cellulose with a bulk density of 0.23 g/cm ³ or less, sugar alcohol, and alpha-gelatinized starch. However, this document does not describe an orally disintegrating tablet containing edoxaban and organic acids.

Furthermore, Patent Document 2 describes the invention of a levofloxacin-containing tablet containing levofloxacin and hydroxypropylcellulose, which has excellent disintegration and suspendability in water. However, There is no record of an orally disintegrating tablet containing edoxaban, organic acid and hydroxypropyl cellulose.

On the other hand, Patent Document 3 describes an invention regarding a coated tablet prepared by containing at least one selected from the group consisting of hypromellose, methylcellulose, ethylcellulose, and hydroxypropylcellulose. One or more coatings of polyvinyl alcohol and polyvinyl alcohol will contain (a) edoxaban, its pharmacologically acceptable salts, or their solvates, (b) selected from sugar alcohols and Coated pharmaceutical compositions characterized by one or more water-swelling additives with improved dissolution properties, and tablets containing (c) a water-swelling additive in addition to the above (a) and (b) Become. However, the subject of this document is to obtain a pharmaceutical composition containing edoxaban with improved dissolution properties. It does not describe a pharmaceutical composition containing edoxaban and an organic acid that has both high disintegration and dissolution properties in water. Orally disintegrating tablets of sex.

Patent Document 4 describes a preparation containing (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, and (B) an organic acid with improved dissolution properties, but it does not describe a preparation containing Orally disintegrating tablets that combine high disintegration properties with water and sufficient hardness to withstand physical impact during manufacturing, transportation, and use.

Prior technical literature patent documents

Patent Document 1 U.S. Patent Application Publication No. 2015/110880 Specification

Patent Document 2 Japanese Patent No. 5295506

Patent Document 3 U.S. Patent No. 9149532 Specification

Patent Document 4 U.S. Patent No. 9402907 Specification

The object of the present invention is to provide an orally disintegrating tablet, which contains edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, and which disintegrates rapidly when held in the mouth or when put into water. When generally produced, , has sufficient hardness during transportation and use, and has excellent storage stability.

As a result of intensive studies conducted by the present inventors in order to solve the above problems, it was found that: (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, (B) an organic acid, (C) An orally disintegrating tablet containing a water-soluble polymer and a disintegrating agent (D) in which the total weight of the tablet is 0.1 to 2.0% by weight has solved the above problems, and thus the present invention has been completed.

That is, the present invention provides a tablet containing (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, (B) an organic acid, and (C) 0.1 to 2.0 weight based on the total weight of the tablet. Orally disintegrating tablets containing % water-soluble polymer and (D) disintegrating agent and its manufacturing method.

That is, the present invention relates to the following (1) to (24).

(1) An orally disintegrating tablet containing: (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, (B) an organic acid, and (C) a total weight of edoxaban relative to the total weight of the tablet. 0.1~2.0% by weight of water-soluble polymer and (D) disintegrating agent.

(2) The orally disintegrating tablet as described in (1), wherein (B) the organic acid is one or more components selected from the group consisting of fumaric acid, alginic acid, and aspartic acid.

(3) The orally disintegrating tablet as described in (1), wherein (B) the organic acid is fumaric acid.

(4) The orally disintegrating tablet as described in any one of (1) to (3), wherein the content of (B) organic acid is 0.1 to 15% by weight relative to the total weight of the tablet.

(5) The orally disintegrating tablet as described in any one of (1) to (4), wherein (C) the water-soluble polymer is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose. One or more components from the group consisting of cellulose, polyvinylpyrrolidone, and polyvinyl alcohol.

(6) The orally disintegrating tablet according to any one of (1) to (4), wherein (C) the water-soluble polymer is hydroxypropyl cellulose.

(7) The orally disintegrating tablet as described in any one of (1) to (6), wherein (D) the disintegrating agent is selected from the group consisting of carboxymethylcellulose (carmellose), crospovidone (crospovidone) , carboxymethylcellulose calcium, croscarmellose sodium, corn starch, sodium starch glycolate, and α-starch.

(8) The orally disintegrating tablet according to any one of (1) to (6), wherein (D) the disintegrating agent is carboxymethylcellulose, crospovidone, and alpha-starch.

(9) The orally disintegrating tablet according to (7) or (8), which further contains sugar alcohol and crystalline cellulose with a bulk density of 0.26 g/cm ³ or less.

(10) The orally disintegrating tablet according to (9), wherein the sugar alcohol is D-mannitol.

(11) The orally disintegrating tablet according to any one of (8) to (10), wherein the average degree of alpha-gelatinization of the alpha-gelatinized starch is 90% or less.

(12) An orally disintegrating tablet, which contains: (A) edoxaban, its pharmacologically acceptable salt, or a solvate thereof, (B) an organic acid, (C) relative to the total weight of the tablet: 0.1~2.0% by weight of hydroxypropyl cellulose, (E) carboxymethyl cellulose, (F) D-mannitol, (G) crystalline cellulose with a bulk density of 0.26g/ ^cm3 or less, and (H) ) α-starch.

(13) The orally disintegrating tablet as described in (12), which contains a drug-containing mixed powder or drug-containing granules, and a drug-free mixed powder; wherein the drug-containing mixed powder or drug-containing granules contain ( A) Edoxaban, its pharmacologically acceptable salts, or solvates thereof, (B) organic acids, (C) 0.1 to 2.0% by weight of hydroxypropyl cellulose based on the total weight of the tablet, and (E) Drug-containing mixed powder or drug-containing granules of carboxymethylcellulose. The drug-free mixed powder contains (F) D-mannitol and (G) a bulk density of 0.26g/ ^cm3 or less. Drug-free mixed powder of crystalline cellulose and (H) α-starch.

(14) The orally disintegrating tablet as described in (12), which contains a drug-containing mixed powder or drug-containing granules, and a drug-free granule; wherein the drug-containing mixed powder or drug-containing granules contain (A ) Edoxaban, its pharmacologically acceptable salts, or solvates thereof, (B) organic acid, (C) 0.1 to 2.0% by weight of hydroxypropyl cellulose based on the total weight of the tablet, and ( E) Drug-containing mixed powder or drug-containing granules of carboxymethylcellulose. The drug-free granules contain (F) D-mannitol and (G) crystalline fibers with a bulk density of 0.26g/ ^cm3 or less. Drug-free granules of starch, and (H) alpha-starch.

(15) The orally disintegrating tablet as described in (12), which contains drug-containing granules and drug-free granules, wherein the drug-containing granules contain (A) edoxaban, its pharmacologically acceptable salt, or the Solvates of the same, (B) organic acids, (C) 0.1 to 2.0% by weight of hydroxypropylcellulose based on the total weight of the tablet, and (E) drug-containing particles of carboxymethylcellulose, The drug-free granules are drug-free granules containing (F) D-mannitol, (G) crystalline cellulose with a bulk density of 0.26 g/cm ³ or less, and (H) α-starch.

(16) The orally disintegrating tablet according to any one of (12) to (15), wherein (B) the organic acid is selected from the group consisting of fumaric acid, alginic acid, and aspartic acid. 1 or more ingredients.

(17) The orally disintegrating tablet according to any one of (12) to (15), wherein (B) the organic acid is fumaric acid.

(18) The orally disintegrating tablet as described in any one of (12) to (17), further comprising: selected from the group consisting of crospovidone, calcium carboxymethylcellulose, and croscarmellose. One or more ingredients from the group consisting of sodium, corn starch, sodium starch glycolate, and alpha-starch.

(19) The orally disintegrating tablet according to any one of (12) to (17), further containing crospovidone.

(20) The orally disintegrating tablet according to any one of (12) to (19), wherein the organic acid is 0.1 to 15% by weight relative to the total weight of the tablet.

(21) The orally disintegrating tablet according to any one of (12) to (20), wherein the crystalline cellulose is 1 to 50% by weight relative to the total weight of the tablet.

(22) The orally disintegrating tablet according to any one of (12) to (21), wherein the average degree of alpha-gelatinization of the alpha-gelatinized starch is 90% or less.

(23) The orally disintegrating tablet according to any one of (12) to (22), which disintegrates within 60 seconds in a disintegration test.

(24) A method for manufacturing orally disintegrating tablets, which includes: by mixing (A) edoxaban, its pharmacologically acceptable salts, or their solvates, (B) fumaric acid and (E) ) carboxymethyl cellulose, and spraying (C) hydroxypropyl cellulose dissolved in water at 0.1 to 2.0% by weight relative to the total weight of the tablet to produce drug-containing granules; by mixing (F) D-mannitol and (G) crystalline cellulose with a bulk density of 0.26g/ ^cm3 or less, and (H) alpha-starch dissolved or dispersed in water are sprayed to produce drug-free granules The steps; and the step of compressing and molding the two obtained particles.

(25) A method for manufacturing orally disintegrating tablets, which includes: by mixing (A) edoxaban, its pharmacologically acceptable salt, or a solvate thereof, (B) fumaric acid, (C) ) of 0.1 to 2.0% by weight of hydroxypropyl cellulose and (E) carboxymethylcellulose relative to the total weight of the tablet, and spraying water to produce drug-containing granules; by mixing ( F) D-mannitol and (G) crystalline cellulose with a bulk density of 0.26g/ ^cm3 or less, and spraying (H) alpha-starch dissolved or dispersed in water to produce drug-free granules step; and the step of compressing and molding the two obtained particles.

According to the present invention, an orally disintegrating tablet can be provided, which contains edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, and has rapid disintegration, solubility, and taste when placed in the oral cavity or in water. It is good, has sufficient hardness during general manufacturing, transportation, and use, and has excellent storage stability.

Furthermore, according to the present invention, a manufacturing method can be provided, which does not require complicated steps or special equipment, and can manufacture the above-mentioned orally disintegrating tablets with excellent characteristics through general compression molding.

Form used to implement the invention

The orally disintegrating tablets in the present invention are compression molded products that have rapid disintegration and solubility when held in the mouth or put into water. Specifically, it means that in a disintegration test using saliva mainly in the oral cavity or a disintegration test using a device, it is usually 5 to 180 seconds, preferably 5 to 60 seconds, and further preferably 5 ~Tablets that disintegrate in about 40 seconds.

The orally disintegrating tablet of the present invention has sufficient hardness during general manufacturing, transportation, and use processes. For example, in the hardness test, an orally disintegrating tablet usually has a hardness of 2 kg or more, preferably 3 kg or more, further preferably 5 kg or more.

The orally disintegrating tablet of the present invention maintains dissolution properties suitable for pharmaceuticals. For example, in a dissolution test, an orally disintegrating tablet usually shows an average dissolution rate of more than 80% and preferably a dissolution rate of more than 85% at the 30-minute time point.

The edoxaban used in the present invention is N ^1- (5-chloropyridin-2-yl)-N ² -((1S,2R,4S)-4-[(dimethyl) represented by the following formula (1) methylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl) Ethylenediamide (hereinafter, may be described as compound 1).

Compound 1 may be a solvate (including hydrates), a pharmacologically acceptable salt, or a solvate (including hydrates) thereof. The pharmacologically acceptable salts thereof or solvates thereof are suitably N ^1- (5-chloropyridin-2-yl)-N ² -((1S,2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl )carbonyl]amino}cyclohexyl)ethylenediamide p-toluenesulfonic acid monohydrate (edoxaban tosylate hydrate).

Edoxaban used in the present invention exhibits a thrombosis inhibitory effect by selectively, reversibly and directly inhibiting activated blood coagulation factor X (activated blood coagulation factor X or FXa). The factor has the function of generating thrombin from prothrombin in the blood coagulation cascade and promoting the formation of fibrin, thereby forming thrombus.

According to clinical trials conducted at home and abroad, edoxaban used in the present invention has been used to treat venous thrombosis in patients undergoing lower limb orthopedic surgeries including total knee replacement, total hip replacement, and hip fracture surgery. It is also used to inhibit the onset of embolism, to inhibit the onset of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation, and to treat venous thromboembolism (deep vein thrombosis and pulmonary thromboembolism). and recurrence suppression.

The edoxaban contained in the orally disintegrating tablets of the present invention can inhibit the onset of ischemic stroke and systemic embolism, as well as venous thromboembolism (deep vein thrombosis and In the treatment of pulmonary thromboembolism (Pulmonary Thromboembolism) and the suppression of recurrences, edoxaban is usually administered orally once a day at a dosage of 30 mg (when the body weight is less than 60 kg) or 60 mg (when the body weight exceeds 60 kg) for adults. . In addition, the dosage can be reduced to 30 mg once a day depending on renal function and concomitant medication. In addition, to suppress the onset of venous thromboembolism in patients undergoing lower limb orthopedic surgery, 30 mg of edoxaban is usually administered orally once a day to adults.

The "acid" in the present invention refers to a compound that exhibits acidity and can be added to pharmaceuticals, and includes organic acids and inorganic acids.

The "organic acid" in the present invention refers to an organic compound showing acidity that can be used as a pharmaceutical additive. Examples of organic acids include carboxylic acid, sulfonic acid, enol, and salts thereof.

"Acidic" in the present invention means that the pH (hydrogen ion index) in the aqueous solution is less than 7; "neutral" means that the pH is 7.

The inorganic acid used in the orally disintegrating tablet of the present invention is not particularly limited as long as it is an inorganic acid that can be added to pharmaceuticals, but examples thereof include hydrochloric acid and phosphoric acid.

The salt of an inorganic acid used in the orally disintegrating tablet of the present invention is not particularly limited as long as it is a salt of an inorganic acid that can be added to pharmaceuticals, but examples thereof include sodium bisulfite, potassium dihydrogen phosphate, and phosphoric acid. Sodium dihydrogen.

The carboxylic acid used in the orally disintegrating tablet of the present invention is not particularly limited as long as it can be added to pharmaceuticals, but examples thereof include adipic acid, aspartic acid, alginic acid, benzoic acid, and carboxyl acid. Ethylene polymer, carboxymethylcellulose, citric acid, glutamic acid, succinic acid, acetic acid, tartaric acid, sorbic acid, lactic acid, hydroxypropylmethylcellulose acetate succinate, tranbutyl Enedioic acid, maleic acid, malonic acid, anhydrous citric acid, methacrylic acid copolymer, or malic acid; preferably, adipic acid, aspartic acid, alginic acid, carboxyvinyl polymer, carboxymethyl cellulose, citric acid, tartaric acid, hydroxypropyl methylcellulose acetate succinate, fumaric acid, maleic acid, malonic acid, methacrylic acid copolymer or malic acid; preferably Examples include aspartic acid, alginic acid, carboxymethylcellulose, and fumaric acid.

The salt of carboxylic acid used in the orally disintegrating tablet of the present invention is not particularly limited as long as it is a carboxylic acid salt that can be added to pharmaceuticals, but examples thereof include sodium L-aspartate, sodium benzoate, and carboxymethyl. Sodium starch, potassium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium dihydrogen citrate, disodium citrate, calcium gluconate, sodium L-glutamate, cross-linked carboxylate Sodium methylcellulose, monosodium succinate, calcium acetate, vinyl acetate resin, sodium tartrate, potassium hydrogen tartrate, potassium sorbate, calcium lactate, monosodium fumarate, sodium stearyl fumarate (sodium stearyl fumarate), anhydrous sodium citrate or sodium malate; preferably sodium carboxymethyl starch, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, cross-linked carboxymethyl starch Sodium methylcellulose or sodium stearyl fumarate; more preferably potassium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium or stearyl fumarate Sodium diphosphate.

The enol used in the orally disintegrating tablet of the present invention is not particularly limited as long as it can be added to pharmaceuticals. Examples thereof include ascorbic acid and erythorbic acid; ascorbic acid is preferably used.

The enol salt used in the orally disintegrating tablet of the present invention is not particularly limited as long as it can be added to pharmaceuticals, but examples include sodium ascorbate or sodium erythorbate; a preferred example is sodium ascorbate.

Examples of the carboxylic acid or salt thereof that is solid at room temperature and used in the orally disintegrating tablet of the present invention include adipic acid, aspartic acid, alginic acid, benzoic acid, carboxyvinyl polymer, carboxymethyl Cellulose, citric acid, glutamic acid, succinic acid, tartaric acid, sorbic acid, hydroxypropyl methylcellulose acetate succinate, fumaric acid, maleic acid, malonic acid, anhydrous citric acid, Methacrylic acid copolymer, malic acid, sodium L-aspartate, sodium benzoate, sodium carboxymethyl starch, potassium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, dicitrate Sodium hydrogen citrate, disodium citrate, calcium gluconate, sodium L-glutamate, croscarmellose sodium, monosodium succinate, calcium acetate, vinyl acetate resin, sodium tartrate, potassium hydrogen tartrate, sorbic acid Potassium, calcium lactate, sodium fumarate, sodium stearyl fumarate, anhydrous sodium citrate, sodium malate; preferably adipic acid, aspartic acid, alginic acid, and carboxyethylene Polymer, carboxymethyl cellulose, citric acid, tartaric acid, hydroxypropyl methylcellulose acetate succinate, fumaric acid, maleic acid, malonic acid, methacrylic acid copolymer, malic acid , sodium carboxymethyl starch, potassium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium or sodium stearyl fumarate; preferably Examples include carboxymethylcellulose, fumaric acid, potassium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium or stearyl fumarate Sodium diphosphate. Preferred examples include aspartic acid, alginic acid, carboxymethyl cellulose, and fumaric acid.

The amount of acid (appropriately organic acid) contained in the orally disintegrating tablet of the present invention is not particularly limited, but it can be determined by those with ordinary knowledge in the technical field to which the invention belongs by referring to the disintegration test and hardness described in this specification. It should be appropriately determined according to the test benchmark in order to exhibit the desired disintegration and hardness. Per 100% by weight of orally disintegrating tablets, 0.1 to 30% by weight is preferred, and 0.1 to 15% by weight is more preferred.

As for the water-soluble polymer in the present invention, for example, one or a combination of two or more selected from the following can be cited: such as hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, carboxymethylcellulose Cellulose derivatives such as cellulose sodium; synthetic polymers such as polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, carboxyvinyl polymer, polyvinyl alcohol, polyethylene glycol (macrogol), etc. ;Acacia gum, agarwood, gelatin, sodium alginate. The water-soluble polymer used in the present invention is preferably a cellulose derivative, and more preferably hydroxypropyl cellulose.

The above-mentioned hydroxypropylcellulose is not limited as long as it maintains the desired properties (disintegration time, hardness, dissolution) as an orally disintegrating tablet. However, commercially available ones include, for example, those produced by Nippon Soda Co., Ltd. sells L grade (viscosity = 6~10mPa.S) or H grade (viscosity = 1000~4000mPa.S).

From the viewpoint of formability and water-disintegrating and suspending properties, the content of the water-soluble polymer in the tablets of the present invention is usually 0.1 to 3.0 wt% per 100% by weight of orally disintegrating tablets, which is relatively high. The optimum range is 0.1~2.0% by weight, and the particularly preferred range is 0.1~0.7% by weight. When the content of the water-soluble polymer is too high, the time required for suspension is prolonged, and the suitability as an orally disintegrating tablet is reduced.

In addition to the above-mentioned components, the orally disintegrating tablets of the present invention may further contain excipients.

Examples of excipients include organic excipients and inorganic excipients selected from sugars, sugar alcohols, starches, and celluloses, but sugar alcohols and/or celluloses are preferred.

Examples of the saccharide include one selected from the group consisting of lactose, sucrose, fructo-oligosaccharide, glucose, palatinose, maltose, reduced maltose, powdered sugar, powdered starch syrup, fructose, isomerized lactose, and honey sugar. or a combination of two or more.

Examples of sugar alcohols include D-mannitol, erythritol, xylitol, maltitol, sorbitol, and the like, with D-mannitol, erythritol, and xylitol being preferred. Further, Preferred is D-mannitol. As for D-mannitol, those that comply with Japanese, European and American pharmacopoeias can usually be used. The crystal form, particle size and specific surface area of the blended D-mannitol are not particularly limited, but the crystal form can be any of α-type, β-type, δ-type, and amorphous, and the particle size is preferably 10 μm. 250 μm or less, more preferably 20 μm or more and 150 μm or less, the specific surface area is preferably 0.1 m ² /g or more and 4 m ² /g or less, more preferably 0.1 m ² /g or more and 2 m ² /g or less; crystal form, particle size and The specific surface area can be measured by, for example, X-ray diffraction method, laser diffraction particle size measurement method, or BET type specific surface area measurement method (multi-point method). Examples of commercial sellers include D-mannitol from Merck, Roquette, Towa Kasei, Kao, and the like.

The blending amount of the above-mentioned sugar alcohol can be appropriately selected. In the case of using D-mannitol, per 100% by weight of orally disintegrating tablets, it is usually 20 to 95% by weight, preferably 30 to 85% by weight.

The above-mentioned sugar alcohols can be directly mixed with other ingredients in powder form to form tablet powders and then subjected to compression molding, or they can also be granulated using an appropriate binding agent and then used for compression molding.

Examples of cellulose include, in addition to crystalline cellulose, those selected from the group consisting of powdered cellulose, low-substitution hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, and cross-linked carboxymethyl cellulose. One or a combination of two or more sodium sodium. The bulk density of crystalline cellulose is usually about 0.10 to 0.46 g/cm ³ , preferably 0.10 to 0.42 g/cm ³ , and further preferably 0.10 to 0.26 g/cm ³ . Examples of commercially available products include Ceolus KG-1000 (bulk density 0.10 to 0.15 g/cm ³ ), Ceolus KG-802 (bulk density 0.13 to 0.23 g/cm ³ ), and Ceolus UF-711 (bulk density 0.20 ~0.26g/cm ³ ) (above, manufactured by Asahi Kasei Chemicals). Alternatively, two or more crystalline celluloses with different bulk densities may be combined and adjusted to obtain a desired bulk density.

The blending amount of the crystalline cellulose per 100% by weight of orally disintegrating tablets is preferably 1 to 50% by weight. If it exceeds 50% by weight, fluidity may deteriorate and manufacturability may decrease. A better blending amount is 5~30% by weight.

The blending ratio of the above-mentioned crystalline cellulose and sugar alcohol is when D-mannitol is used as the sugar alcohol. The sugar alcohol is 1 to 10 parts by weight, preferably 1.5 to 8.5, relative to 1 part by weight of crystallized cellulose. parts by weight, preferably 2 to 3 parts by weight.

The above-mentioned crystalline cellulose can be directly mixed with other ingredients in a powder state to form a tablet powder and subjected to compression molding, or it can also be granulated using an appropriate binder and then used for compression molding.

Examples of the starches include one type or a combination of two or more types selected from corn starch, potato starch, rice starch, and alpha-gelated starch.

Examples of inorganic excipients include one or more selected from the group consisting of synthetic hydrotalcite, precipitated calcium carbonate, hydrous silica, light anhydrous silicic acid, magnesium aluminum silicate, and magnesium hydroxide. combination.

In addition to the above-mentioned components, the orally disintegrating tablets of the present invention may further contain a disintegrating agent.

Examples of the disintegrating agent include crospovidone (for example, a Japanese Pharmacopoeia-compliant product), carboxymethylcellulose calcium (for example, a Japanese Pharmacopoeia-compliant product), carboxymethylcellulose (for example, a Japanese Pharmacopoeia-compliant product), Croscarmellose sodium (e.g. Japanese Pharmacopoeia compliant product), low substitution hydroxypropyl cellulose (e.g. Japanese Pharmacopoeia compliant product), corn starch (e.g. Japanese Pharmacopoeia compliant product), sodium starch glycolate (e.g. Japanese Pharmacopoeia compliant product) Compliant products), and one or more combinations of α-starch; particularly preferably selected from the group consisting of crospovidone, carboxymethylcellulose calcium, carboxymethylcellulose, and low-substitution hydroxypropylcellulose. , and one or a combination of two or more α-starches. More preferred is a combination of carboxymethyl cellulose, crospovidone, and α-starch.

The above-mentioned α-gelatinized starch is obtained by heat-processing starch to α-gelatinize it, and also includes partially α-gelatinized starch. In addition, as the above-mentioned α-gelatinized starch, those described in Japanese Pharmaceutical Additive Standards can be used. The average alpha degree is preferably 90% or less, more preferably 70 to 80%. Among commercially available ones, for example, α-gelatinized starch Swelstar PD-1 (manufactured by Asahi Kasei Chemical Co., Ltd.) can be used.

The blending amount of the above-mentioned α-starch is based on 100% by weight of orally disintegrating tablets, usually 1 to 15% by weight, preferably 1 to 10% by weight.

The α-starch can be directly mixed with other ingredients in powder form to form tablet powder and compressed for molding. It can also be granulated together with other ingredients and then used for compression molding.

In the orally disintegrating tablet of the present invention, the α-starch functions as a disintegrating agent. On the other hand, when produced, it exhibits viscosity when dissolved or dispersed in a liquid (such as water). Therefore, when sprayed, When the raw materials are in a powdery state, they can be granulated and made into granules. Taking advantage of this property, tablets with good formability and desired intraoral disintegration properties can be obtained by spraying a solution or dispersion in which α-starch is dissolved or dispersed in water until it contains A powdered mixture of crystalline cellulose and sugar alcohols with a bulk density of 0.26g/cm3 ^or less is subjected to fluidized bed granulation to produce granules, which are mixed with other ingredients as needed and compressed. The advantages of such production are the unique properties of α-starch, which are basically unobtainable when using conventional disintegrating agents such as low-substituted hydroxypropyl cellulose and crospovidone.

The blending amount of the above-mentioned disintegrating agent is per 100% by weight of oral disintegrating tablets, usually 0.5~20% by weight, preferably 2~20% by weight.

The orally disintegrating tablets of the present invention may contain various additives commonly used in the manufacture of tablets as long as the effects of the invention are not impaired.

Examples of additives include binding agents, lubricants, coating agents, plasticizers, colorants, flavors, sweeteners, flavoring agents, fluidizers, foaming agents, surfactants, and the like.

Examples of the binding agent include gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, polytriglucose (pullulan), methylcellulose, and hydroxypropyl One or a combination of two or more of cellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and polyethylene glycol.

Examples of the lubricant include magnesium stearate (for example, Japanese Pharmacopoeia-compliant product), calcium stearate (for example, Japanese Pharmacopoeia-compliant product), and sodium stearyl fumarate (for example, pharmaceutical additive standard). Compliant products) and talc (such as Japanese Pharmacopoeia compliant products) or a combination of two or more thereof, particularly preferably magnesium stearate.

The blending amount of lubricant is per 100% by weight of orally disintegrating tablets, preferably 0.1 to 5.0% by weight.

Examples of the coating agent that coats the surface of the powdered drug (crystalline surface) or the particle surface of the granulated drug include ethyl cellulose, aminoalkyl methacrylate copolymer E, methyl Acrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, methacrylic acid aminoalkyl ester copolymer RS, methacrylic acid aminoalkyl ester copolymer RS, acrylic acid One or a combination of two or more of ethyl ester‧methyl methacrylate copolymer, polyvinyl acetal‧diethylamino acetate and polyvinyl acetate resin.

The plasticizer combined with the coating agent may be selected from the group consisting of diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol and glyceryl triacetate. (triacetin) or a combination of two or more.

Examples of the coloring agent include food colorings selected from Edible Yellow No. 5, Edible Red No. 2, Edible Blue No. 2, etc.; edible lake pigments, yellow ferric oxide, ferric oxide, titanium oxide, One or a combination of two or more β-carotene and riboflavin.

Examples of the flavoring agent include one type or a combination of two or more types selected from citrus, lemon, strawberry, mint, menthol, menthol micron, and various fragrances.

Examples of the sweetener include sodium saccharin, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, sucralose, and stevia. ) and thaumatin or a combination of two or more.

Examples of the flavoring agent include one or a combination of two or more selected from the group consisting of sodium chloride, magnesium chloride, disodium cinnamate, sodium L-glutamate, and honey.

Examples of the fluidizing agent include one selected from the group consisting of hydrous silica, light anhydrous silicic acid, and talc, or a combination of two or more thereof.

Examples of the foaming agent include tartaric acid and/or anhydrous citric acid.

Examples of the surfactant include polyoxyethylene 40 stearate, sorbitan fatty acid ester, polyoxyethylene hardened castor oil, polysorbate, and glycerin monostearate. One or a combination of two or more esters and sodium lauryl sulfate.

The orally disintegrating tablets of the present invention can be produced by using well-known manufacturing methods for solid preparations. For example, the main drug, additives, etc. can also be granulated together, and then a lubricant, etc. can be added and mixed to form a tablet. and obtain tablets. In addition, after granulation, operations such as drying and granulation can be performed as needed. Hereinafter, one aspect (Aspects A and B) of the orally disintegrating tablet of the present invention and its manufacturing method will be described.

Aspect A: Combining drug-free granules (hereinafter, described as rapidly disintegrating granules) containing crystalline cellulose, sugar alcohols, and α-starch with a bulk density of 0.26 g/cm ³ or less and drugs, or The drug-containing granules are compressed and molded to obtain orally disintegrating tablets.

In this aspect, the drug-free particles function as a skeleton of the preparation, which can impart desired disintegration properties and formability as an orally disintegrating tablet. Drug-free granules exhibit excellent disintegration and moldability even if they are blended with only three components: crystalline cellulose, sugar alcohol, and α-starch with a bulk density of 0.26g/ ^cm3 or less. Other additives may be blended as needed. Furthermore, the orally disintegrating tablet in this aspect exhibits further excellent disintegration and dissolution properties by adding 0.1 to 2.0% by weight of water-soluble polymer and organic acid relative to the total weight of the tablet.

The manufacturing method of the orally disintegrating tablet of aspect A includes: a step of manufacturing drug-free granules (A-1); a step of manufacturing drug-containing granules (A-2); and combining the drug-free granules, drugs or The step of mixing drug-containing granules and other additives and performing compression molding (A-3).

A-1: Steps to manufacture drug-free granules

Drug-free particles can be produced using the following methods 1) or 2).

1) A method of wet granulating a mixture containing crystalline cellulose with a bulk density of 0.26g/ ^cm3 or less, sugar alcohol (such as D-mannitol) and alpha-gelatinized starch using water.

2) Granulate a mixture containing crystalline cellulose and sugar alcohol (such as D-mannitol) with a bulk density of 0.26g/cm ^{or less} using a liquid obtained by dissolving or dispersing α-starch in water or the like. method.

Here, for granulation, conventional extrusion granulation, mixing and stirring granulation, high-speed stirring granulation, fluidized bed granulation, or rotational granulation, etc. can be used.

Alphalated starch exhibits a viscosity suitable for granulation when dissolved or dispersed in a liquid such as water. Examples of granulation methods include: a method of directly mixing α-starch in a powdered state with other ingredients and using water to granulate; and a method of granulating using a liquid obtained by dissolving or dispersing α-starch in water. . Any of these methods will provide tablets with the desired properties, but the latter method is preferred.

In addition, when granulating using a liquid that dissolves or disperses the pregelatinized starch, either the high-speed stirring granulation method or the fluidized bed granulation method can be applied. However, when granules are produced by the fluidized bed granulation method, More excellent orally disintegrating tablets can be obtained. When other additives such as conventional disintegrating agents are blended into the granules that do not contain the drug, they may be blended into the mixture before granulation.

The blending ratio of crystalline cellulose with a bulk density of 0.26 g/ ^cm3 or less and sugar alcohol in drug-free granules is based on 1 part by weight of crystalline cellulose when D-mannitol is used as the sugar alcohol. , the sugar alcohol is 1.5~8.5 parts by weight, preferably 2~3 parts by weight.

A-2: Steps for manufacturing drug-containing granules

The drug can be maintained in the form of a powder, or can be made into granules as desired and then mixed with granules without the drug. Drug-containing granules can be produced by conventional extrusion granulation, mixing and stirring granulation, high-speed stirring granulation, fluidized bed granulation, or rotational granulation.

For example, a liquid obtained by dissolving or dispersing hydroxypropyl cellulose in water can be used to combine powdered or granular drugs, organic acids, crystalline cellulose with a bulk density of 0.26 g/ ^cm3 or less, and sugar alcohols. The powder is mixed and granulated to prepare drug-containing granules. In addition, water can also be used to granulate a mixed powder of powdered or granular drugs, organic acids, crystalline cellulose with a bulk density of 0.26g/cm ^or less, sugar alcohols and hydroxypropyl cellulose to produce a drug-containing drug. particles.

In order to mask unpleasant tastes and odors such as bitterness or irritation, or to control dissolution, drugs or drug-containing granules may be coated. For coating, the aforementioned coating agents and plasticizers can be used appropriately. The coating method is by using, for example, a fluidized bed granulating and coating machine, a rotating fluidized bed granulating and coating machine, a centrifugal flow type granulating and coating machine, and a Wurster type fluidized bed granulating and coating machine. Clothes machine to do it.

When two or more kinds of drugs are used, the drugs may be contained in the same granules or in separate granules according to their blending suitability, and then subjected to compression molding.

A-3: The step of mixing drug-free granules with drugs or drug-containing granules and other additives and performing compression molding

The drug-free granules are mixed with the drug or drug-containing granules, and the desired disintegrating agent, lubricant, and other additives, and are compressed and molded to prepare an orally disintegrating tablet. Mixing is performed by using, for example, a drum mixer or a convection mixer. The drug can also be mixed with other additives to be used as a drug-containing mixed powder.

The compression molding of the orally disintegrating tablets of the present invention can be carried out using a general tableting machine. The forming pressure of the tablet machine can be the same as that for ordinary tablets, and it also depends on the shape and size of the tablets, but it is preferably about 2 to 20 kN, and more preferably about 4 to 14 kN.

The blending ratio of drug-free granules to the total weight of tablet ingredients only needs to be 30 to 90%. In the case where the drug is in powder form, the blending ratio is 30~70%, preferably 30~60%. When the drug is granulated and used, the blending ratio is 30 to 70%, preferably 30 to 60%. Furthermore, when the drug is granulated and used, the blending weight ratio of the drug-free granules and the drug-containing granules is preferably 1 for the drug-containing granules and 0.5 to 2.0 for the drug-containing granules.

Aspect B: Oral disintegration obtained by compressing and molding a drug-free mixed powder containing crystalline cellulose, sugar alcohol and alpha-starch with a bulk density of 0.26g/ ^cm3 or less, and drugs or drug-containing granules. tablets.

In this aspect, the drug-free mixed powder provides the desired disintegration properties and formability as an orally disintegrating tablet. The drug-free mixed powder exhibits excellent disintegration and moldability even if it contains only three components: crystalline cellulose, sugar alcohol, and α-starch with a bulk density of 0.26g/ ^cm3 or less. Other additives can be blended as needed. Furthermore, the orally disintegrating tablet in this aspect exhibits further excellent disintegrating properties and dissolution properties by adding 0.1 to 2.0% by weight of water-soluble polymers and organic acids.

The manufacturing method of the orally disintegrating tablet of aspect B includes: the steps of manufacturing drug-containing granules as desired; and the steps of mixing the drug or drug-containing granules and other additives and performing compression molding. The steps for producing drug-containing granules are the same as A-2 above.

In the step of mixing the drug or drug-containing granules and other additives and performing compression molding, the mixing or compression molding step is the same as A-3 above.

The orally disintegrating tablet of the present invention thus obtained has excellent disintegration properties and solubility when placed in the oral cavity or in water, and is also excellent in physical and chemical stability.

The disintegration or solubility of the orally disintegrating tablet of the present invention is based on the disintegration and dissolution time in the oral cavity (the tablet does not contain water in the mouth of a healthy adult man and completely disintegrates or dissolves only under saliva). time) is usually 5 to 180 seconds, preferably 5 to 60 seconds, and further preferably about 5 to 40 seconds.

The orally disintegrating tablets of the present invention are gradually disintegrated or dissolved by saliva when held in the mouth, through the pressure in the oral cavity, that is, the pressure caused by the jaw and tongue, or the friction caused by the tongue, that is, " "licking" movements, etc., and disintegrate or dissolve in a shorter time. For people with dry mouth or low saliva, it can be disintegrated and dissolved in the mouth with water or hot water, or it can be taken directly with water like ordinary tablets.

On the other hand, the hardness of the orally disintegrating tablets of the present invention also has sufficient hardness after a stability test under certain temperature and humidity conditions (for example, temperature 25°C, humidity 75%, open system, 1 week).

Therefore, it has a hardness that does not collapse during the manufacturing steps and distribution process of the preparation, has a practical hardness even when stored under certain temperature and humidity conditions, and has excellent storage stability.

The orally disintegrating tablets of the present invention can be used to treat diseases and can be used as a preparation that is easy to take by the elderly, children or patients with swallowing difficulties, and can also be used as a safe preparation for general adults.

[Example]

The following examples are for illustrative purposes and are not intended to limit the invention to these examples.

[Comparative Example 1-1]

Into a fluidized bed granulation dryer (FLO-2 model manufactured by Freund Corporation), 384.9 g of edoxaban tosylate hydrate, 355.1 g of D-mannitol (Pearlitol 50C manufactured by Roquette Corporation), and crystallized 95.24 g of cellulose (Ceolus UF-711, manufactured by Asahi Kasei Chemical Co., Ltd.), 95.24 g of crospovidone (Kollidon CL-F, manufactured by BASF), and carboxymethyl cellulose (NS-300, manufactured by Gotoku Pharmaceutical Co., Ltd.) 57.14g, and spray a combined solution in which 12.38g of hydroxypropylcellulose (HPC-H, manufactured by Nippon Soda) was dissolved in 1364g of purified water, and then dried to obtain granules (drug-containing particles). Furthermore, 18480 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation) and 8360 g of crystalline cellulose (Ceolus KG-1000, manufactured by Asahi Kasei Chemicals) were put into a fluidized bed granulation dryer (GPCG-15 manufactured by Powrex). A liquid obtained by dispersing 1,100 g of α-gelatinized starch (swelstar PD-1 manufactured by Asahi Kasei Chemicals Co., Ltd.) in 12,650 g of purified water was sprayed and then dried to obtain granulated materials (quickly disintegrating granules). Further, 600.0 g of the obtained drug-containing granules, 451.4 g of rapidly disintegrating granules, 68.57 g of crospovidone (Kollidon CL-F, manufactured by BASF), and 22.86 g of magnesium stearate (HyQual 5712, manufactured by Mallinckrodt) were added. g After mixing, the mixture was tableted using a rotary tableting machine (Kikusui Seisakusho, VIRGO) at a tableting pressure of 5 kN to obtain an orally disintegrating tablet (11 mmφ, 400 mg).

[Example 1-1]

Into a fluidized bed granulation dryer (FLO-2 type, manufactured by Freund), 392.6 g of edoxaban tosylate hydrate, 384.6 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation), and crystal fibers were put in 95.24g of element (Ceolus UF-711, manufactured by Asahi Kasei Chemicals), 5.714g of fumaric acid (manufactured by Merck), 57.14g of crospovidone (Kollidon CL-F, manufactured by BASF), and carboxymethylcellulose ( NS-300 manufactured by Gotoku Pharmaceutical Co., Ltd.) 57.14g and 7.619g of hydroxypropylcellulose (HPC-H manufactured by Japan Soda Co., Ltd.) dissolved in 839.0g of purified water were sprayed and dried. Thereby, granules (drug-containing granules) are obtained. Furthermore, 18480 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation) and 8360 g of crystalline cellulose (Ceolus KG-1000, manufactured by Asahi Kasei Chemicals) were put into a fluidized bed granulation dryer (GPCG-15 manufactured by Powrex). Then, a liquid obtained by dispersing 1,100 g of α-gelatinized starch (swelstar PD-1 manufactured by Asahi Kasei Chemicals Co., Ltd.) in 12,650 g of purified water was sprayed and then dried to obtain granulated materials (quickly disintegrating granules). Furthermore, 600.0 g of the obtained drug-containing granules, 437.7 g of rapidly disintegrating granules, 68.57 g of crospovidone (Kollidon CL-F manufactured by BASF), 13.71 g of sucralose (manufactured by San-EI GEN F.F.I.), and After mixing 22.86 g of magnesium stearate (HyQual 5712 manufactured by Mallinckrodt), the mixture was tableted using a rotary tableting machine (VIRGO, Kikusui Seisakusho) at a tableting pressure of 5 kN to obtain an orally disintegrating tablet (11 mmφ, 400 mg).

[Example 1-2]

Into a fluidized bed granulation dryer (FLO-2 type manufactured by Freund), 392.6 g of edoxaban tosylate hydrate, 371.2 g of D-mannitol (Pearlitol 50C manufactured by Roquette Corporation), and crystal fiber were put in 95.24g of element (Ceolus UF-711, manufactured by Asahi Kasei Chemicals), 19.05g of fumaric acid (manufactured by Merck), 57.14g of crospovidone (Kollidon CL-F, manufactured by BASF), and carboxymethylcellulose ( NS-300 manufactured by Gotoku Pharmaceutical Co., Ltd.) 57.14g and 7.619g of hydroxypropylcellulose (HPC-H manufactured by Japan Soda Co., Ltd.) dissolved in 839.0g of purified water were sprayed and dried. Thereby, granules (drug-containing granules) are obtained. Furthermore, 18480 g of D-mannitol (Pearlitol 50, manufactured by Roquette Corporation) and 8360 g of crystalline cellulose (Ceolus KG-1000, manufactured by Asahi Kasei Chemicals) were put into a fluidized bed granulation dryer (GPCG-15 manufactured by Powrex). Then, a liquid obtained by dispersing 1,100 g of α-gelatinized starch (swelstar PD-1 manufactured by Asahi Kasei Chemicals Co., Ltd.) in 12,650 g of purified water was sprayed and then dried to obtain granulated materials (quickly disintegrating granules). Furthermore, 600.0 g of the obtained drug-containing granules, 437.7 g of rapidly disintegrating granules, 68.57 g of crospovidone (Kollidon CL-F manufactured by BASF), 13.71 g of sucralose (manufactured by San-EI GEN F.F.I.), and After mixing 22.86 g of magnesium stearate (HyQual 5712 manufactured by Mallinckrodt), the mixture was tableted using a rotary tableting machine (VIRGO, Kikusui Seisakusho) at a tableting pressure of 5 kN to obtain an orally disintegrating tablet (11 mmφ, 400 mg).

[Example 1-3]

Into a fluidized bed granulation dryer (FLO-2 type, manufactured by Freund), 384.9 g of edoxaban tosylate hydrate, 171.3 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation), and crystal fibers were put in 95.24g of element (Ceolus UF-711, manufactured by Asahi Kasei Chemicals), 228.6g of fumaric acid (manufactured by Merck), 57.14g of crospovidone (Kollidon CL-F, manufactured by BASF), and carboxymethylcellulose ( NS-300) 57.14g, and 629.2g of purified water was dissolved in a combined solution of 5.714g hydroxypropylcellulose (HPC-H, manufactured by Nippon Soda), sprayed, and then dried. This results in granules (drug-containing granules). Furthermore, 18480 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation) and 8360 g of crystalline cellulose (Ceolus KG-1000, manufactured by Asahi Kasei Chemicals) were put into a fluidized bed granulation dryer (GPCG-15 manufactured by Powrex). Then, a liquid obtained by dispersing 1,100 g of α-gelatinized starch (swelstar PD-1 manufactured by Asahi Kasei Chemicals Co., Ltd.) in 12,650 g of purified water was sprayed and then dried to obtain granulated materials (quickly disintegrating granules). Further, 600.0 g of the obtained drug-containing granules, 451.4 g of rapidly disintegrating granules, 68.57 g of crospovidone (Kollidon CL-F, manufactured by BASF), and 22.86 g of magnesium stearate (HyQual 5712, manufactured by Mallinckrodt) were prepared. After mixing, the mixture was tableted using a rotary tableting machine (Kikusui Seisakusho, VIRGO) at a tableting pressure of 5 kN to obtain an orally disintegrating tablet (11 mmφ, 400 mg).

[Comparative Example 2-1]

Into a fluidized bed granulation dryer (FLO-2 model manufactured by Freund Corporation), 384.9 g of edoxaban tosylate hydrate, 355.1 g of D-mannitol (Pearlitol 50C manufactured by Roquette Corporation), and crystallized 95.24 g of cellulose (Ceolus UF-711, manufactured by Asahi Kasei Chemical Co., Ltd.), 95.24 g of crospovidone (Kollidon CL-F, manufactured by BASF), and carboxymethyl cellulose (NS-300, manufactured by Gotoku Pharmaceutical Co., Ltd.) 57.14g, and spray a combined solution in which 12.38g of hydroxypropylcellulose (HPC-H, manufactured by Nippon Soda) was dissolved in 1364g of purified water, and then dried to obtain granules (drug-containing particles). Furthermore, 18480 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation) and 8360 g of crystalline cellulose (Ceolus KG-1000, manufactured by Asahi Kasei Chemicals) were put into a fluidized bed granulation dryer (GPCG-15 manufactured by Powrex). Then, a liquid obtained by dispersing 1,100 g of α-gelatinized starch (swelstar PD-1 manufactured by Asahi Kasei Chemicals Co., Ltd.) in 12,650 g of purified water was sprayed and then dried to obtain granulated materials (quickly disintegrating granules). Further, 600.0 g of the obtained drug-containing granules, 451.4 g of rapidly disintegrating granules, 68.57 g of crospovidone (Kollidon CL-F, manufactured by BASF), and 22.86 g of magnesium stearate (HyQual 5712, manufactured by Mallinckrodt) were added. g After mixing, tableting was performed with a rotary tableting machine (Kikusui Seisakusho, VIRGO) at a tableting pressure of 5 kN to obtain an orally disintegrating tablet (11 mmφ, 400 mg).

[Comparative Example 2-2]

Into a fluidized bed granulation dryer (FLO-2 type manufactured by Freund), 384.9 g of edoxaban tosylate hydrate, 352.3 g of D-mannitol (Pearlitol 50C manufactured by Roquette Corporation), and crystal fiber were put in 95.24g of element (Ceolus UF-711, manufactured by Asahi Kasei Chemicals), 5.714g of fumaric acid (manufactured by Merck), 57.14g of crospovidone (Kollidon CL-F, manufactured by BASF), and carboxymethylcellulose ( NS-300 manufactured by Gotoku Pharmaceutical Co., Ltd.) 57.14g, and 47.62g of hydroxypropyl cellulose (HPC-L manufactured by Japan Soda Co., Ltd.) dissolved in 632.9g of purified water was sprayed and dried. Thereby, granules (drug-containing granules) are obtained. Furthermore, 18480g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation) and 8360g of crystalline cellulose (Ceolus KG-1000, manufactured by Asahi Kasei Chemicals) were put into a fluidized bed granulation dryer (GPCG-15 manufactured by Powrex). Then, a liquid obtained by dispersing 1,100 g of α-gelatinized starch (swelstar PD-1 manufactured by Asahi Kasei Chemicals Co., Ltd.) in 12,650 g of purified water was sprayed and then dried to obtain granulated materials (quickly disintegrating granules). Further, 330.0 g of the obtained drug-containing granules, 248.3 g of rapidly disintegrating granules, 37.71 g of crospovidone (Kollidon CL-F, manufactured by BASF), and 12.60 g of magnesium stearate (HyQual 5712, manufactured by Mallinckrodt) were prepared. After mixing, tableting was performed with a rotary tableting machine (Kikusui Seisakusho, 18HUK) at a tableting pressure of 5 kN to obtain an orally disintegrating tablet (11 mmφ, 400 mg).

[Comparative Example 2-3]

Into a fluidized bed granulation dryer (FLO-2 type, manufactured by Freund), 384.9 g of edoxaban tosylate hydrate, 352.3 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation), and crystal fibers were put in 95.24g of element (Ceolus UF-711, manufactured by Asahi Kasei Chemicals), 5.714g of fumaric acid (manufactured by Merck), 57.14g of crospovidone (Kollidon CL-F, manufactured by BASF), and carboxymethylcellulose ( NS-300) 57.14g, and 47.62g of hydroxypropylcellulose (HPC-H, manufactured by Nippon Soda) dissolved in 3920g of purified water was sprayed and dried. This results in granules (drug-containing granules). Furthermore, 18480 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation) and 8360 g of crystalline cellulose (Ceolus KG-1000, manufactured by Asahi Kasei Chemicals) were put into a fluidized bed granulation dryer (GPCG-15 manufactured by Powrex). Then, a liquid obtained by dispersing 1,100 g of α-gelatinized starch (swelstar PD-1 manufactured by Asahi Kasei Chemicals Co., Ltd.) in 12,650 g of purified water was sprayed and then dried to obtain granulated materials (quickly disintegrating granules). Further, 330.0 g of the obtained drug-containing granules, 248.3 g of rapidly disintegrating granules, 37.71 g of crospovidone (Kollidon CL-F, manufactured by BASF), and 12.60 g of magnesium stearate (HyQual 5712, manufactured by Mallinckrodt) were prepared. After mixing, tableting was performed with a rotary tableting machine (Kikusui Seisakusho, 18HUK) at a tableting pressure of 5 kN to obtain an orally disintegrating tablet (11 mmφ, 400 mg).

[Example 2-1]

Into a fluidized bed granulation dryer (FLO-2 type, manufactured by Freund), 384.9 g of edoxaban tosylate hydrate, 392.3 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation), and crystal fibers were put in 95.24g of element (Ceolus UF-711, manufactured by Asahi Kasei Chemicals), 5.714g of fumaric acid (manufactured by Merck), 57.14g of crospovidone (Kollidon CL-F, manufactured by BASF), and carboxymethylcellulose ( 57.14g of NS-300, manufactured by Gotoku Pharmaceutical Co., Ltd., and 7.619g of hydroxypropyl cellulose (HPC-L, manufactured by Japan Soda Co., Ltd.) dissolved in 101.3g of purified water were sprayed and dried. Thereby, granules (drug-containing granules) are obtained. Furthermore, 18480 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation) and 8360 g of crystalline cellulose (Ceolus KG-1000, manufactured by Asahi Kasei Chemicals) were put into a fluidized bed granulation dryer (GPCG-15 manufactured by Powrex). Then, a liquid obtained by dispersing 1,100 g of α-gelatinized starch (swelstar PD-1 manufactured by Asahi Kasei Chemicals Co., Ltd.) in 12,650 g of purified water was sprayed and then dried to obtain granulated materials (quickly disintegrating granules). Further, 330.0 g of the obtained drug-containing granules, 248.3 g of rapidly disintegrating granules, 37.71 g of crospovidone (Kollidon CL-F, manufactured by BASF), and 12.60 g of magnesium stearate (HyQual 5712, manufactured by Mallinckrodt) were prepared. After mixing, tableting was performed with a rotary tableting machine (Kikusui Seisakusho, 18HUK) at a tableting pressure of 5 kN to obtain an orally disintegrating tablet (11 mmφ, 400 mg).

[Example 2-2]

Into a fluidized bed granulation dryer (FLO-2 type, manufactured by Freund), 392.6 g of edoxaban tosylate hydrate, 384.6 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation), and crystal fibers were put in 95.24g of element (Ceolus UF-711, manufactured by Asahi Kasei Chemicals), 5.714g of fumaric acid (manufactured by Merck), 57.14g of crospovidone (Kollidon CL-F, manufactured by BASF), and carboxymethylcellulose ( It was sprayed with a combined solution of 7.619g of hydroxypropyl cellulose (HPC-H, manufactured by Japan Soda) dissolved in 839.0g of purified water, and then dried. Thereby, granules (drug-containing granules) are obtained. Furthermore, 18480g of D-mannitol (Pearlitol 50C, manufactured by Roquette Corporation) and 8360g of crystalline cellulose (Ceolus KG-1000, manufactured by Asahi Kasei Chemicals) were put into a fluidized bed granulation dryer (GPCG-15 manufactured by Powrex). Then, a liquid obtained by dispersing 1,100 g of α-gelatinized starch (swelstar PD-1 manufactured by Asahi Kasei Chemicals Co., Ltd.) in 12,650 g of purified water was sprayed and then dried to obtain granulated materials (quickly disintegrating granules). Furthermore, 600.0 g of the obtained drug-containing granules, 437.7 g of rapidly disintegrating granules, 68.57 g of crospovidone (Kollidon CL-F manufactured by BASF), 13.71 g of sucralose (manufactured by San-EI GEN F.F.I.), and After mixing 22.86 g of magnesium stearate (HyQual 5712 manufactured by Mallinckrodt), the mixture was tableted using a rotary tableting machine (VIRGO, Kikusui Seisakusho) at a tableting pressure of 5 kN to obtain an orally disintegrating tablet (11 mmφ, 400 mg).

[Comparative Example 3-1]

Using a mortar, mix 16.16 g of edoxaban tosylate hydrate, 15.92 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Co., Ltd.), and 4.0 grams of crystalline cellulose (Ceolus UF-711, manufactured by Asahi Kasei Chemical Co., Ltd.) g mixing, thereby obtaining a mixture (drug-containing mixed powder). 36.08 g of the obtained drug-containing mixed powder and 0.72 g of magnesium stearate (Mallinckrodt, HyQual 5712) were mixed, and further 0.1 g of fumaric acid (Nippon Shokubai) and hydroxypropyl cellulose ( After mixing 0.1 g of HPC-L (manufactured by Nippon Soda Co., Ltd.), it was tableted using a desktop tablet forming machine (Ichihashi Seiki, HANDTAB) at a tableting pressure of 10 kN to obtain an orally disintegrating tablet (8.0 mmφ, 194 mg).

[Comparative Example 3-2]

Using a mortar, 16.16 g of edoxaban tosylate hydrate, 15.92 g of D-mannitol (Pearlitol 50C, manufactured by Roquette Co., Ltd.), and 4.0 g of crystalline cellulose (Ceolus UF-711, manufactured by Asahi Kasei Chemical Co., Ltd.) were mixed together in a mortar. Mix, thereby obtaining a mixture (drug-containing mixed powder). 36.08 g of the obtained drug-containing mixed powder and 0.72 g of magnesium stearate (HyQual 5712, manufactured by Mallinckrodt) were mixed, and further 0.1 g of crospovidone (Kollidon CL-F, manufactured by BASF) and carboxymethyl fiber were mixed After mixing 0.1 g of Su (NS-300, manufactured by Ohtoku Pharmaceutical Co., Ltd.), tableting was performed with a desktop tablet forming machine (Ichihashi Seiki, HANDTAB) at a tableting pressure of 10 kN to obtain an orally disintegrating tablet (8.0 mmφ, 194mg).

[Example 3-1]

Into a fluidized bed granulation dryer (FLO-2 type manufactured by Freund), 392.6 g of edoxaban tosylate hydrate, 371.2 g of D-mannitol (Pearlitol 50C manufactured by Roquette Corporation), and crystal fiber were put in 95.24g of element (Ceolus UF-711, manufactured by Asahi Kasei Chemicals), 19.05g of fumaric acid (manufactured by Merck), 57.14g of crospovidone (Kollidon CL-F, manufactured by BASF), and carboxymethylcellulose ( NS-300) 57.14g, and 839.0g purified water was dissolved in a combined solution of 7.619g hydroxypropyl cellulose (HPC-H, manufactured by Nippon Soda), sprayed, and then dried. This results in granules (drug-containing granules). Furthermore, 18480 g of D-mannitol (Pearlitol 50, manufactured by Roquette Corporation) and 8360 g of crystalline cellulose (Ceolus KG-1000, manufactured by Asahi Kasei Chemicals) were put into a fluidized bed granulation dryer (GPCG-15 manufactured by Powrex). Then, a liquid obtained by dispersing 1,100 g of α-gelatinized starch (swelstar PD-1 manufactured by Asahi Kasei Chemicals Co., Ltd.) in 12,650 g of purified water was sprayed and then dried to obtain granulated materials (quickly disintegrating granules). Furthermore, 600.0 g of the obtained drug-containing granules, 437.7 g of rapidly disintegrating granules, 68.57 g of crospovidone (Kollidon CL-F manufactured by BASF), 13.71 g of sucralose (manufactured by San-EI GEN F.F.I.), and After mixing 22.86 g of magnesium stearate (HyQual 5712 manufactured by Mallinckrodt), the mixture was tableted using a rotary tableting machine (VIRGO, Kikusui Seisakusho) at a tableting pressure of 5 kN to obtain an orally disintegrating tablet (11 mmφ, 400 mg).

[Evaluation method]

The tablets obtained in Examples and Comparative Examples were evaluated by the following method.

Tablet thickness and hardness were measured using a fully automatic tablet measuring device (Type WHT-2, PHARMA TEST APPARATEBAU GmbH) (the average value of 20 tablets is recorded).

The disintegration test was measured with reference to the "Disintegration Test Method" of the 16th revised edition of the Japanese Pharmacopoeia (each maximum value for 6 tablets is recorded).

The dissolution test was conducted in accordance with Method 2 (paddle method, 50 rpm) described in the Japanese Pharmacopoeia. Regarding the dissolution rate, the average dissolution rate of 6 tablets was calculated. The dissolution test solution (pH 6.0) is used by adding an appropriate amount of citric acid solution (0.025mol/L) to disodium hydrogen phosphate solution (0.05mol/L) and adjusting it to pH 6.0.

The results are shown in Table 1 to Table 5.

[Brief explanation of the results]

Table 1: Compared with the formulation without fumaric acid as in Comparative Example 1-1, when fumaric acid is blended as in Examples 1-1 to 1-3, in 60 seconds It disintegrates quickly within the tablet and exerts its superior function as an oral disintegrating tablet. In addition, the higher the blending ratio of fumaric acid, the faster the disintegration time and dissolution properties can be ensured.

Table 2: Comparison with the formulation without blending fumaric acid as in Comparative Example 2-1, and the formulation with a large blending amount of hydroxypropyl cellulose as in Comparative Examples 2-2 and 2-3. , in a formulation that blends fumaric acid and a small amount of hydroxypropyl cellulose as in Examples 2-1 and 2-2, it shows a rapid disintegration time within 60 seconds, and exerts As an oral disintegrating tablet, it has more excellent functions. Furthermore, at this time, regardless of the physical properties of hydroxypropylcellulose, rapid disintegration time was shown.

Table 3: A formula similar to Comparative Example 3-1 even though fumaric acid and hydroxypropyl cellulose are blended but not blended with a disintegrating agent, and a formulation similar to Comparative Example 3-2 even though blended with a disintegrating agent. Compared with the formulation of powder without blending fumaric acid and hydroxypropylcellulose, when a disintegrant, fumaric acid, and a small amount of hydroxypropylcellulose are blended as in Example 3-1 , showing a rapid disintegration time within 60 seconds, and exerting a more excellent function as an oral disintegrating tablet.

Table 4 and Table 5: According to the manufacturing method described in Examples 1 to 3 and the prescription described in Table 4, the orally disintegrating tablet of Example 4 was produced. As in Examples 4-1 to 4-9, when fumaric acid, a small amount of hydroxypropyl cellulose, and a disintegrating agent are mixed with edoxaban, a rapid disintegration time within 60 seconds is shown, and the effect is As a more excellent function of orally disintegrating tablets, it can further ensure rapid dissolution.

Table 6 and Table 7 describe an example of the prescription of the present invention.

Claims (6)

An orally disintegrating tablet, which contains drug-containing granules and drug-free granules; wherein the drug-containing granules contain (A) edoxaban (edoxaban), its pharmacologically acceptable salts, or their solvates The drug-free granules include: The system contains (F) D-mannitol, (G) crystalline cellulose with a bulk density of 0.26 g/cm ³ or less, and (H) α-gelatinized starch. The orally disintegrating tablet of claim 1 further contains crospovidone. For example, the orally disintegrating tablet of claim 1, wherein (B) fumaric acid is 0.1 to 15% by weight relative to the total weight of the tablet. For example, the oral disintegrating tablets of any one of claims 1 to 3 disintegrate within 60 seconds in the disintegration test. A method for manufacturing orally disintegrating tablets, which includes: by mixing (A) edoxaban, its pharmacologically acceptable salts, or their solvates, (B) fumaric acid and (E) carboxymethyl The step of manufacturing drug-containing granules by spraying (C) 0.1 to 2.0% by weight of hydroxypropyl cellulose dissolved in water relative to the total weight of the tablet; by mixing (F) The step of producing drug-free granules by spraying D-mannitol and (G) crystalline cellulose with a bulk density of 0.26g/ ^cm3 or less, and (H) alpha-starch dissolved or dispersed in water; and a step of compressing and molding the two obtained particles. A method for manufacturing orally disintegrating tablets, which includes: by mixing (A) edoxaban, its pharmacologically acceptable salts, or their solvates, (B) fumaric acid, (C) relative to The total weight of the tablet is 0.1~2.0% by weight of hydroxypropyl cellulose and (E) carboxymethyl cellulose, and spraying water to produce drug-containing granules; by mixing (F) D-manna Sugar alcohols and (G) crystalline cellulose with a bulk density of 0.26g/ ^cm3 or less, and spraying (H) alpha-starch dissolved or dispersed in water to produce drug-free granules; and The steps of compressing and molding two types of particles.